1. Field of the Invention
The present invention relates to the use of 5,6-diisobutyroyloxy-2-methylaminotetralin in the preparation of pharmaceutical compositions for the therapy of cardiac disorders, particularly congestive heart failure.
2. Discussion of the Background
Notwithstanding the therapeutical progresses of the last years, congestive heart failure is still one of the main death causes.
The symptomatic therapy usually aims at reducing the workload of the decompensed heart and improving the mechanical function.
Recently, cardiac failure has been proved to be related to important biochemical and neurohumoral changes involving different factors.
In fact, when cardiac output diminishes, compensatory mechanisms act in the body in order to maintain the circulatory homeostasis.
In heart failure, vasoconstriction associated with the activation of said mechanisms cause an increase in peripheral vascular resistance.
As a consequence, the after-load increases which can in turn further strain the already weakened heart, triggering a vicious circle which leads to a progress of the pathology.
This generalized vasoconstriction is mainly caused by the activation of the sympathetic nervous system consequent to the increase of plasma catecholamines, particularly adrenalin, which is an early signal of cardiac decompensation.
A close relationship between degree of sympathetic activation and severity of the disease seems to exist, and a direct connection between noradrenaline plasmatic levels and mortality seems moreover established.
Therefore, the therapy of congestive heart failure has to be directed to the improvement of the hemodynamic factors, on one hand, and to the pharmacological modulation of the neurohumoral system on the other.
Dopaminergic drugs appear as candidates to become established as drugs for heart failure in the majority of patients.
In particular, dopamine has peculiar characteristics, compared with the other medicaments, since it stimulates both dopaminergic and alpha and beta-adrenergic receptors.
Two types of dopaminergic receptors exist: those located on the smooth muscle of the vascular system (DA1 receptors) which mediate vasodilation in the renal, mesenteric, cerebral and coronary districts, and those in pre-synaptic position (DA2 receptors), which inhibit noradrenaline release from post-ganglionic sympathetic nerve endings to blood vessels and heart.
The usefulness of dopamine in the treatment of heart failure is, however, restricted by it being inactive orally.
Analogously dobutamine, a synthetic analogue of dopamine, can be used only intravenously.
Aminotetralin derivatives have been studied for a long time as dopamine structural analogues for any uses as medicaments.
However, none of these compounds has up to now been introduced in therapy.
One of them, 5,6-dihydroxy-2-methylaminotetralin hydrobromide, is disclosed as a coronary vasodilator in U.S. Pat. No. 4,134,997 in the name of Joseph G. Cannon.
Cannon administered the compound to dogs at a rate of approximately 10 xcexcg/kg animal weight per minute (range 8.5-13.9) by a continuous intravenous infusion and demonstrated a substantial increase in coronary blood flow.
5,6-Diisobutyroyloxy-2-methylaminotetralin, hereinafter referred to as CHF 1035, has been described first in GB Pat. 2123410 among a series of aminotetralin derivatives disclosed as potential antibronchospastic due to their activity on adrenergic receptors.
Both 5,6-dihydroxy-2-methylaminotetralin (hereinafter indicated with the experimental abbreviations CHF 1024) and CHF 1035 have been formerly characterized as compounds having prevailing selective activity on xcex22 adrenergic receptors.
Now it has been surprisingly found that CHF 1024 and CHF 1035, in addition to the already known xcex22 agonist activity, have remarkable peripheral DA2 and xcex12 presynaptic activities leading to a reduction of the sympathetic tone, which is elevated in heart failure patients.
Studies carried out in the animal proved that CHF 1024 and CHF 1035 have a vasodilating activity due the combination of their effects on xcex12 and xcex22 and DA1/DA2 receptors as well as a cardiac isotropic activity.
They are effective at a very low doses, even by oral route.
The peripheral xcex12 adrenergic and peripheral DA2 dopaminergic activities of the aminotetralin derivatives of the present invention have never been described until now.
On the contrary, it was previously affirmed by Hilditch A. and Drew G. M. in European Journal of Pharmacology vol. 72, pages 287-296, 1981 that the compound 5,6-dihydroxy-2-methylaminotetralin was inactive as dopamine receptor agonist in relaxing splenic artery strips.
We have demonstrated that both CHF 1024 and CHF 1035 have agonist activity on dopaminergic receptors and that they are selective for the presynaptic DA2 ones.
The xcex12 adrenergic and DA2-dopaminergic activities of the compounds have been evaluated in binding tests (example 1 and 3), in isolated neuronally-simulated rat vas deferens (example 2) and in rabbit rectococcygeus muscle (example 4).
The cardiovascular effects of the compounds have been evaluated in vivo in anesthetized rats both after intravenous and intraduodenal administration (example 5 )